E F Choo1, P W Angus, D J Morgan. 1. Department of Pharmaceutics, Victorian College of Pharmacy, Monash University, Melbourne, Australia.
Abstract
BACKGROUND/AIMS: There is evidence to suggest that not all pathways of drug metabolism are similarly affected in cirrhosis. The effect of cirrhosis on drug oxidation and glucuronidation has been extensively investigated but little is known of the effect of cirrhosis on drug sulphation. The aim of this study was to investigate the effect of cirrhosis on sulphation. METHODS: We investigated the effect of cirrhosis on p-nitrophenol sulphation and compared this with the effect of cirrhosis on p-nitrophenol glucuronidation as well as on d-propranolol oxidation simultaneously in the single-pass isolated perfused rat liver. The perfusate contained added inorganic sulphate to maximise production of p-nitrophenol sulphate. RESULTS: About 77% and 59% of p-nitrophenol was eliminated as the sulphate conjugate by the healthy (n=6) and cirrhotic (n=7) livers, respectively. Mean total p-nitrophenol clearance was decreased in cirrhosis (healthy: 18.5+/-0.2 vs. cirrhotic 15.3+/-4.0 ml/min; p<0.05). The decrease in total clearance of p-nitrophenol was due solely to the decrease in sulphate formation clearance, which was significantly decreased (healthy: 14.1+/-1.9 vs. cirrhotic: 9.27+/-3.33 ml/min; p<0.05). Mean glucuronide formation clearance (healthy: 5.11+/-0.94 vs cirrhotic: 5.79+/-0.85 ml/ min; p>0.05) was not significantly altered. Mean total propranolol clearance was decreased in cirrhosis (healthy: 19.9+/-0.1 vs. cirrhotics: 18.0+/-1.5 ml/min; p<0.05). CONCLUSIONS: We have shown that in cirrhosis there is significant impairment of drug oxidation and sulphation, whilst glucuronidation is spared. The decreased sulphation of p-nitrophenol was most likely due to a decrease in phenol sulphotransferase and/or decrease in cofactor synthesis.
BACKGROUND/AIMS: There is evidence to suggest that not all pathways of drug metabolism are similarly affected in cirrhosis. The effect of cirrhosis on drug oxidation and glucuronidation has been extensively investigated but little is known of the effect of cirrhosis on drug sulphation. The aim of this study was to investigate the effect of cirrhosis on sulphation. METHODS: We investigated the effect of cirrhosis on p-nitrophenol sulphation and compared this with the effect of cirrhosis on p-nitrophenol glucuronidation as well as on d-propranololoxidation simultaneously in the single-pass isolated perfused rat liver. The perfusate contained added inorganic sulphate to maximise production of p-nitrophenol sulphate. RESULTS: About 77% and 59% of p-nitrophenol was eliminated as the sulphate conjugate by the healthy (n=6) and cirrhotic (n=7) livers, respectively. Mean total p-nitrophenol clearance was decreased in cirrhosis (healthy: 18.5+/-0.2 vs. cirrhotic 15.3+/-4.0 ml/min; p<0.05). The decrease in total clearance of p-nitrophenol was due solely to the decrease in sulphate formation clearance, which was significantly decreased (healthy: 14.1+/-1.9 vs. cirrhotic: 9.27+/-3.33 ml/min; p<0.05). Mean glucuronide formation clearance (healthy: 5.11+/-0.94 vs cirrhotic: 5.79+/-0.85 ml/ min; p>0.05) was not significantly altered. Mean total propranolol clearance was decreased in cirrhosis (healthy: 19.9+/-0.1 vs. cirrhotics: 18.0+/-1.5 ml/min; p<0.05). CONCLUSIONS: We have shown that in cirrhosis there is significant impairment of drug oxidation and sulphation, whilst glucuronidation is spared. The decreased sulphation of p-nitrophenol was most likely due to a decrease in phenol sulphotransferase and/or decrease in cofactor synthesis.